This invention relates to implanted intravenous catheters and, in particular, to techniques for locking such catheters between uses and for prevention of infection.
Intravenous catheters are increasingly used as blood accesses for hemodialysis, plasmapheresis, and for infusion of drugs and nutrients. There are two major complications of intravenous catheters: thrombosis and infection. Both are at least partly related to the method of locking the catheter lumen in periods between uses.
Catheter Locking
Soft, cuffed, single or dual-lumen, central-vein catheters are commonly used as permanent blood accesses. Between uses they are locked by being filled with a fluid to isolate the patient""s vascular system from the environment. To prevent clotting, the entire lumen or lumens of such catheters, from hub to tip, are commonly filled with an anticoagulant in the period between uses. This locking solution is aspirated prior to the next use with a syringe and discarded. If the solution cannot be aspirated, because the catheter lumen is clotted, the solution is pushed into the venous system. Such injection of the locking solution may cause excessive anticoagulation or other side effects.
Heparin is the most commonly used anticoagulant to lock catheters between uses. Each lumen is locked with 5,000 to 10,000 units of heparin after dialysis. This solution must be withdrawn from the catheter before the next use, since this much heparin may result in bleeding if infused into the patient. Heparin exerts its anticoagulant activity mainly through activation of Anti-Thrombin III, and it is effective in concentrations as low as 1 unit per ml of blood. Heparin has no ability to lyse preformed thrombi or fibrin sheaths and has no antibacterial properties. In fact, it may promote growth of bacteria within the xe2x80x9cbiofilmxe2x80x9d layer of protein on catheter surfaces. Also, heparin induces severe loss of platelets and paradoxical clotting in some patients (the xe2x80x9cwhite clotxe2x80x9d syndrome).
Another anticoagulant used for catheter locking is urokinase, which is derived from urine and kidney cells. It is a serine protease composed of two chains joined by a disulfide bridge. The precursor molecule, single-chain urokinase (scu-PA) is also active. Urokinase is inhibited by plasminogen activator inhibitors 1 and 2, and protease nexin-1. A receptor for urokinase on endothelial cells (u-PAR) may modulate urokinase activity by removal of urokinase-plasminogen activator-inhibitor complexes. Both two-chain and single-chain urokinases are more active in the presence of fibrin and heparin. Catheter lumens maybe locked with urokinase to restore the patency of a clotted catheter, or urokinase may be used instead of heparin to prevent clot formation between dialyses. In case of inability to aspirate the locking solution, the injection of 10,000 units of urokinase is harmless, since much higher doses are used systemically to lyse fibrin sheaths formed on the outer surface of the catheter.
Another anticoagulant used for catheter locking is tissue plasminogen activator, which is a single-chain serine protease with a molecular weight of 68 Kda. Tissue plasminogen activator has not been used for routine locking of catheters, but has been used in small doses (1-2 mg) to restore patency of clotted catheter lumens. Injection of this small dose of tissue plasminogen activator present in the catheter lumen has no systemic effect.
Catheter Infections
Infection associated with catheters is a major reason for their removal. The major source of infection in cuffed catheters appears to be contamination of the catheter hub or lumen during connection or disconnection procedures at the start of and completion of hemodialysis. Periluminal migration of bacteria along the external surface of the catheter as a source of infection seems to be less common, since most catheter-associated bacteremias are not combined with exit or tunnel infection. The surfaces of catheters create a conducive environment at which bacteria can grow and impede phagocytosis by white blood cells. Furthermore, the bacteria can produce a biofilm, i.e., a coating of proteins and glycocalyx that protects bacteria from antibiotics and white cells.
None of the aforementioned anticoagulant locking solutions has any significant antibacterial properties and, therefore, none is of any assistance in combating or preventing infection. While it is possible to lock catheters with bactericidal agents, such as concentrated (27%) sodium chloride, 10% povidone iodine, 4% chlorhexidine, or 1% sodium hypochlorite, none of these bactericidal agents has any anticoagulant activity.
If systemic antibiotics are used for treating bacteremia, they will have an antibiotic action while they are present in the catheter, but this occurs only when blood is flowing through the catheter lumen, such as in dialysis. Treatment with systemic antibiotics is frequently ineffective and removal of the catheter becomes necessary, due to persistent bacteremia (caused by catheter colonization) or worsening clinical condition, Catheter removal, however, is not always possible due to the difficulty in creating alternative blood access. Infection also is the major reason for removal of the smaller cuffed central venous catheters used for infusion of drugs or total parenteral nutrition. Their internal surfaces may also be subjected to antibiotic agents, but only during antibiotic infusion.
One approach to salvaging a colonized catheter is the use of flush solutions, i.e., to lock the ports of the catheter with a mixture of an antibiotic and an anticoagulant or thrombolytic agent. The disadvantage of this method is the diffusion of small amounts of antibiotic into the systemic circulation. This may cause induction of resistant organisms, a growing concern for all antibiotics. For this reason, it is unlikely that the Food and Drug Administration (FDA) would approve chronic catheter locking with antibiotics, and the use of antibiotics for infection prophylaxis should be avoided.
Another approach is to use as a locking solution trisodium citrate, which may have both anticoagulant and antibacterial properties. However, while studies have indicated that concentrated trisodium citrate is able to kill or prevent the growth of most bacteria, it seems to have only a weak effect on staphylococcus aureus, which, of the most common microorganisms responsible for catheter-associated infections, is the most virulent and difficult to eradicate without catheter removal. Another disadvantage of catheter locking with concentrated citrate trisodium is its ability to induce transient hypocalcemia, tingling of the fingers and metallic taste when injected into the bloodstream even in small amounts. Even transient hypocalcemia may cause arrhythmia.
It would be possible to inject an anticoagulant agent into the catheter, followed by injection of a non-antibiotic bactericidal agent. However, diffusion would cause mutual dilution of both the anticoagulant agent and the bactericidal agent. Dilution of the anticoagulant should be avoided in order to prevent clot formation at the tip of the catheter. Also, diffusion of the solutions increases the risk of strong bactericidal agents being brought into contact with the blood, a condition which should also be avoided.
As mentioned above, most data indicate that contamination of the catheter hub is the most common etiology of catheter-associated bacteremia. For prevention of intralumenal clot formation it is important to maintain the presence of an anticoagulant at the catheter tip. Thus, ideally, for antibacterial action, the catheter lumen should be filled with bactericidal solution in the external or proximal portion of the lumen (close to the hub), and for prevention of clotting should be filled with anticoagulant solution in the internal or distal part of the lumen (close to the tip). However, for the reasons explained above, the solutions should not mix.
Accordingly, a fundamental aspect of the invention is the locking of a catheter by the use of an anticoagulant agent and an antimicrobial agent with a separator therebetween. More specifically, the invention utilizes an air bubble to separate the anticoagulant and antimicrobial agents.
Another aspect of the invention is the use of a multi-chamber syringe for injection of the locking material into the catheter.
A further aspect of the invention is the use of such a multi-chamber syringe for aspiration of the locking material from the catheter.
A still further aspect of the invention is the provision of a unique multi-chamber syringe suitable for these purposes.
Certain ones of these and other aspects of the invention may be realized by providing a method of preserving the operative condition of an implanted vascular access catheter having inner and outer ends, between uses of gaining access to the vascular system of the patient, the method comprising: inserting an anticoagulant agent through the catheter outer end to drive any blood in the catheter back into the patient vascular system and to fill an inner portion of the catheter with the anticoagulant agent; then inserting a separating substance into the catheter to fill a central portion of the catheter; and then inserting an antimicrobial agent into the catheter to fill an outer portion of the catheter, whereby the separating substance separates the anticoagulant agent from the antimicrobial agent.
Other aspects of the invention maybe realized by providing a syringe comprising an external barrel having an end seal with a discharge opening therein and an internal barrel disposed within the external barrel and having plural separated chambers each having an outlet opening and a plunger, the internal barrel being movable relative to the external barrel among a closed condition wherein the outlet openings are in sealing engagement with the seal and plural injection conditions wherein the outlet openings are respectively disposed in communication with the discharge opening.